The pathogenesis of inhalational anthrax is dependent on the interaction of Bacillus anthracis with alveolar macrophage. The initial germination of the spores occurs within alveolar macrophage which transport the bacterium to lymph nodes. Macrophage are also uniquely sensitive to cytolysis by lethal toxin secreted by B. anthracis and cytokine release by macrophage in response to anthrax lethal toxin mediates the host septic reaction. Genetic differences in toxin sensitivity affecting a protein downstream of the target of lethal toxin have been described for mice. It is the overall hypothesis of this proposal that there are genetic differences in human susceptibility to pathogenesis of B. anthracis which can be identified by gene expression profiling of alveolar macrophage treated by anthrax lethal toxin. The identification of such candidate genes in humans and the verification that these genes play a role in pathogenesis would define potential targets for post infection intervention. Preliminary data is presented indicating differences among individuals in the sensitivity of alveolar macrophage to anthrax toxin and on use the of gene expression microarrays to identify genes that play a critical role in host - bacterium interaction. The objectives of the proposal are: (1) To fully describe the differences in sensitivity of human alveolar macrophage to cytotoxic effects of lethal toxin and spores of B. anthracis and assess if they are physiological or genetic in origin; (2) To assess gene expression in alveolar macrophage and identify candidate genes and pathways that differ among individuals with differing sensitivity to lethal toxin; and (3) To use our extensive experience in adenoviral gene transfer to alveolar macrophage to verify the role of potential lethal toxin susceptibility and resistance genes.